Temperature strongly affects physiology and behavior, and thermosensation is relevant to body temperature homeostasis and pain in humans, host seeking by insect disease vectors, and movement in all animals. Using D. melanogaster as a model system, we propose to define a novel molecular pathway for thermal sensing involving a previously unappreciated class of potential thermal sensing protein. This work will thus lead to the definition of a new molecular pathway for thermal sensing of potentially broad relevance for both basic biology and human health. In preliminary experiments, we have identified a critical regulator of themnosensory behavior. Furthermore, we have found that this protein is capable of conferring thermal sensitivity upon a neuron when ectopically expressed. Together our preliminary data suggest this protein may function as a previously unappreciated type of thermal sensor. We propose to extend these studies in three aims. 1) We will investigate the site of action and molecular nature ofthe putative thermal sensor in controlling thermotactic behavior. 2) We will examine how this putative thermal sensor affects temperature sensing by thermosensory neurons. 3) We will examine the molecular mechanisms by which the thermal sensor detects temperature by examining its potential signaling mechanism and the signaling pathways with which it may interact to transduce temperature infonnation. Together, these studies will provide fundamental new insights into the molecular mechanisms of thermal sensation. RELEVANCE (See instmctions): This proposal investigates the molecular mechanisms of thermal sensation. Thermosensation is critical for animal sun/ival and physiology. In humans, thermosensation is critical for pain, inflammation and tx)dy temperature regulation. Thus, thermosensory mechanisms are of biomedical relevance. In addition, themosensation is important for host-seeking by insect vectors of human diseases like malaria and West Nile. Thus the study of thermosensation is relevant to the control of insect-borne human disease.